Paediatrics (RCH) - Theses
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ItemEarly-life predictors of vascular phenotypes : in the Child Health CheckPoint and Longitudinal Study of Australian Children( 2018)Background: Cardiovascular disease (CVD) is a leading cause of global mortality and morbidity in the 21st century. The main pathological mechanism in CVD, atherosclerosis, begins early in life. Effective CVD prevention strategies require better understanding of the early-life patterns of CVD risk. Aims: In a cohort of Australian 11- to 12-year-old children and their parents, I sought to describe, in the early-life period, patterns in CVD risk factors and vascular phenotypes indicative of atherosclerosis. Specifically, I sought: I. To investigate, through systematic review, whether early-life SEP influences adult inflammation II. To examine whether early-life SEP is associated with child vascular phenotypes III. To examine whether traditional risk factors (BP, body mass index (BMI), glucose, cholesterol, smoking, diet and physical exercise) in the Ideal Cardiovascular Health (ICVH) score, are associated with child vascular phenotypes IV. To determine whether inflammation, measured by glycoprotein acetyls (GlycA), is associated with child risk factors, and to what extent inflammation also predicts child vascular phenotypes Methods: To address the first aim, I conducted a systematic review and meta-analysis of cross-sectional and longitudinal studies examining child SEP and adult inflammation, in particular C-reactive protein (CRP). The next three aims utilised data from the Child Health CheckPoint (n=1874 child-parent dyads, 49% girls, 88% mothers), a biophysical markers cross-sectional study nested within the Longitudinal Study of Australian Children. It was conducted in 2015 sequentially across 15 cities and towns around Australia. Associations were evaluated with multivariable linear regression, supplemented with survey weights and methods and multiple imputation. Adult associations were examined in parallel when equivalent data were available. Results: In addressing the first aim, meta-analysis showed individuals with parents in the lowest SEP bracket had 25% higher CRP levels than those in the highest SEP bracket in age- and sex-adjusted analyses. The inclusion of adult BMI into models attenuated this association. In the following CheckPoint analyses, both family and neighbourhood socioeconomic disadvantage were associated with structural and functional vascular phenotypes at age 11-12 years, in age- and sex-adjusted linear regression analyses. Structural vascular phenotype associations were independent of traditional CVD risk factors, while functional vascular phenotype associations largely attenuated when adjusted for BMI. The absence of adequate grandparental SEP data precluded parallel adult analyses. Further, each additional CVD risk factor at age 11-12 years was cross-sectionally associated with adverse functional, but not structural, vascular phenotypes. Adult associations were larger in magnitude and associations existed for both structural and functional vascular phenotypes. Associations with BP and BMI were largest in magnitude and independent of other CVD risk factors. Finally, in addressing the last aim, I observed GlycA at age 11-12 years was associated with structural and functional vascular phenotypes in age- and sex-adjusted models. Associations attenuated with inclusion of traditional CVD risk factors, specifically BMI and BP. Adult associations were similar, however GlycA remained associated with PWV independent of CVD risk factors. Conclusion: Socioeconomic gradients in childhood were associated with vascular phenotypes and CVD risk factors. These risk factors were themselves associated with functional vascular phenotypes in children. In adults, CVD risk factors were associated with both vascular structure and function. These findings broadly support CVD prevention strategies starting earlier in life. Further investigation of socioeconomic influences on both novel and traditional CVD risk factors may afford opportunities to improve population cardiovascular health.
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ItemVascular phenotypes and innate immune responses following Kawasaki disease and toxic shock syndrome( 2017)Background: The pathogenesis of cardiovascular disease begins in early life. Inflammation is increasingly recognised to play a pivotal role in the initiation and progression of atherosclerotic cardiovascular disease. It is unclear whether acute childhood vascular inflammation results in heightened cardiovascular risk and reflects an underlying increased inflammatory predisposition. Understanding the host immune susceptibility determinants and the impact of early life vascular inflammation on the subsequent development of subclinical atherosclerosis could assist in improving diagnostics, prognostication, and treatment. This thesis focuses on two childhood diseases characterised by acute inflammation involving the cardiovascular system, Kawasaki disease (KD) and toxic shock syndrome (TSS). Aims: Part 1: To identify the macro-and microvascular phenotypes associated with subclinical atherosclerosis in individuals following KD or TSS. Part 2: To investigate differences in innate immune responses following KD or TSS that might underlie host susceptibility. Methods: Part 1: A case-control study of 60 KD, 22 TSS, and 60 control participants; cases were investigated at least two years after their acute illness. Non-invasive measurements of extra-cardiac arterial structure (carotid and aortic intima-media thickness) and function (pulse wave velocity, carotid artery distensibility and diameter compliance) were done. Retinal microvascular parameters were measured in both an Australian and Singaporean cohort. Part 2: In-vitro cytokine production induced by Toll-like receptor and inflammasome ligand stimulation was measured in whole blood. Results: Part 1: Compared to control participants, Individuals following KD had increased aortic intima-media thickness and reduced carotid distensibility, indicative of heightened cardiovascular risk. Furthermore, KD participants, particularly of Asian ethnicity, had wider retinal venules with an incremental increase in those with coronary artery abnormalities, also in keeping with an increase in cardiovascular risk. Individuals following TSS had reduced retinal fractal dimension but no other adverse differences in the macro- and microvascular parameters. Part 2: Compared to control participants, individuals following KD had reduced interleukin (IL)-1 receptor antagonist production in response to stimulation with double stranded RNA and increased IL-6 production in response to incubation with Lyovec™ (a lyophilised cationic lipid-based transfection reagent). Toxic shock syndrome participants had increased pro-inflammatory cytokine production (interferon-, IL-1, IL-6) in response to stimulation with bacterial ligands (peptidoglycan, lipopolysaccharide). Conclusions: Part 1: Extra-cardiac vascular phenotypes indicative of increased cardiovascular risk have been found in individuals following KD. These findings suggest that these individuals should minimise their modifiable cardiovascular risk factors. Limited evidence for increased cardiovascular risk was found following TSS, suggesting that differing causes of childhood vascular inflammation may have varying impact on the development of subclinical atherosclerosis. Part 2: Individuals with previous KD or TSS have decreased anti-inflammatory and increased pro-inflammatory responses (respectively) to innate immune stimulation. The findings indicate either an inherent immunological susceptibility and/or trained innate immunity following the acute illness.